The term avermectin (previously referred to as C-076) is used to describe a series of compounds isolated from the fermentation broth of an avermectin producing strain of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The avermectin compounds are a series of macrolides, each of which is substituted at the 13 position with a 4-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin compounds and the instant derivatives thereof have a very high degree of anthelmintic and anti-parasitic activity. The avermectin series of compounds isolated from the fermentation broth have the following structure: ##STR1## wherein R is the 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrosyl group of the structure: ##STR2## and wherein the broken line indicates a single or a double bond; R.sub.1 is a hydrogen or hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and PA0 R.sub.3 is methoxy or hydroxy PA0 25-(thien-3-yl)-25-de-(2-butyl)avermectin A2a PA0 25-(cyclohex-3-enyl)-25-de-(2-butyl)avermectin A2a PA0 25-cyclohexyl-25-de-(2-butyl)avermectin A2a PA0 25-(1-methylthioethyl)-25-de-(2-butyl)avermectin A2a PA0 25-(2-methylcyclopropyl)-25-de-(2-butyl)avermectin A2a PA0 25-(2-buten-2-yl)-25-de-(2-butyl) avermectin B1a PA0 25-(cyclopentyl)-25-de-(2-butyl)-avermectin B1a PA0 3',3"-O-Bisdesmethyl-25-cyclohexyl25-de-(2-butyl)-avermectin B1a PA0 3',3"-O-Bisdesmethyl-25-cyclopentyl-25-de-(2-butyl)-avermectin B1a PA0 3',3"-O-Bisdesmethyl-25-(3-thienyl)-25-de-(2-butyl)-avermectin B1a PA0 3',3"-O-Bisdesmethyl-25-(3-furyl)-25-de-(2-butyl)-avermectin B1a PA0 3',3"-O-Bisdesmethyl-25-(1-methylthioethyl)-25-de-(2-butyl)-avermectin B1a. PA0 3"-O-Desmethylavermectin B1a/B1b PA0 3'-O-Desmethylavermectin B1a/B1b PA0 R.sub.2 is methyl, ethyl, or an alpha-branched C.sub.3 -C.sub.8 alkyl or alkenyl group; PA0 R.sub.3 is hydrogen, loweralkyl or loweralkanoyl; PA0 R.sub.4 is ##STR5## R.sub.5 is ##STR6## R.sub.6 is hydrogen or loweralkoxy; R.sub.7 is halomethyl, phenylthiomethyl, hydroxymethyl, loweralkoxymethyl, loweralkanoyloxymethyl, aminomethyl, N-loweralkylaminomethyl, N,N-diloweralkylaminomethyl or loweralkanoylaminomethyl; and PA0 R.sub.8 is hydroxy, loweralkanoyloxy; or PA0 R.sub.7 and R.sub.8 together are methylene, or --CH.sub.2 O--; PA0 R.sub.9 is loweralkyl. PA0 R.sub.2 is iso-propyl, sec-butyl, or an alpha-branched C.sub.3 -C.sub.8 alkenyl group; PA0 R.sub.3 is hydrogen; PA0 R.sub.4 is ##STR7## R.sub.5 is ##STR8## R.sub.6 is hydrogen or methoxy: R.sub.7 is iodomethyl, phenylthiomethyl, hydroxymethyl, loweralkoxymethyl, loweralkanoyloxymethyl, aminomethyl, N-loweralkylaminomethyl, N,N-diloweralkylaminomethyl or loweralkanoylaminomethyl; and PA0 R.sub.8 is hydroxy; or PA0 R.sub.7 and R.sub.8 together are methylene, or --CH.sub.2 O--; PA0 R.sub.9 is methyl. PA0 R.sub.2 is iso-propyl, sec-butyl, or an alpha-branched C.sub.3 -C.sub.6 alkenyl group; PA0 R.sub.3 is hydrogen; PA0 R.sub.4 is ##STR9## R.sub.5 is ##STR10## R.sub.6 is hydrogen or methoxy; R.sub.7 is iodomethyl, phenylthiomethyl, hydroxymethyl, loweralkoxymethyl, loweralkanoyloxymethyl, aminomethyl, N-loweralkylaminomethyl, N,N-diloweralkylaminomethyl or loweralkanoylaminomethyl; and PA0 R.sub.8 is hydroxy; or PA0 R.sub.7 and R.sub.8 together are methylene, or --CH.sub.2 O--; PA0 R.sub.9 is methyl. PA0 4"-exomethylene-avermectin B1a/B1b-4", 4"a-oxide isomer a PA0 4"-exomethylene-avermectin B1a/B1b-4", 4"a-oxide isomer b PA0 4"-deoxy-4"-exomethylene-avermectin B1a/B1b PA0 4"-iodomethyl-avermectin B1a/B1b PA0 4"-phenylthiomethyl-avermectin B1a/B1b PA0 4"-exomethylene-avermectin B2a/B2b-4", 4"a-oxide PA0 4"-deoxy-4"-exomethylene-avermectin B2a/B2b PA0 4"-iodomethyl-avermectin B2a/B2b PA0 25-cylopentyl-25-de-(1-methylpropyl)-4"-exomethylene-avermectin B1a-4", 4"a-oxide PA0 22,23-dihydro-4"-exomethylene-avermectin B1a/B1b-4", 4"a-oxide PA0 R.sub.10 is loweralkyl, phenyl, or loweralkyl substituted phenyl and Y is halogen. The reduction is completely described in U.S. Pat. No. 4,199,569.
There are eight different avermectin natural product compounds and they are given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b based upon the structure of the individual compounds.
In the foregoing structural formula, the individual avermectin compounds are as set forth below. (The R group is 4'-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose):
______________________________________ C.sub.22 -C.sub.23 R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a (22,23-double bond) -- sec-butyl --OCH3 A1b (22,23-double bond) -- iso-propyl --OCH3 A2a (22,23-single bond) OH sec-butyl --OCH3 A2b (22,23-single bond) OH iso-propyl --OCH3 B1a (22,23-double bond) -- sec-butyl --OH B1b (22,23-double bond) -- iso-propyl --OH B2a (22,23-single bond) OH sec-butyl --OH B2b (22,23-single bond) OH iso-propyl --OH ______________________________________
The avermectin compounds are generally isolated as mixtures of a and b components. Such compounds differ only in the nature of the R2 substituent and the minor structural differences have been found to have very little effect on the isolation procedures, chemical reactivity and biological activity of such compounds.
In addition to these natural avermectins containing the 25-iso-propyl or 25-sec-butyl-substituent, closely related derivatives containing other branched or cyclic 25-alkyl or 25-alkenyl substituents, optionally further substituted by heteroatoms such as oxygen, sulfur, nitrogen, halogen and the like are known in the literature. These derivatives are obtained through various adjustments and additions to the fermentation procedures as described fully in the European Patent Publications EPO 0 214 731, and 0 284 176.
Avermectins are products of microbial fermentations using the actinomycete Streptomyces avermitilis. These microbes use acetates and propionates as building blocks for most of the avermectin carbon chain, which is then further modified by microbial enzymes to give the completed avermectin molecules. It is known, however, that the carbon C-25 and the 2-propyl and 2-butyl substituents at this carbon are not derived from acetate or propionate units, but are derived from aminoacids L-valine and L-isoleucine, respectively. It is believed that these aminoacids are deaminated to the corresponding 2-ketoacids, and that these then are decarboxylated to give 2-methylpropionic and 2-methylbutyric acids. These acids are then directly incorporated into the avermectin structures to give the 2-propyl and 2-butyl C-25 substituents, as is reported by Chen et al., Abstr. Pap. Am. Chem. Soc. (186 Meet., MBTD 28, 1983). It was also disclosed in European Patent Publication numbers 0 214 731 and 0 284 176 that additions of large amounts of other acids such as cyclopentanoic, cyclobutyric, 2-methylpentanoic, 2-methylhexanoic, thiophene-3-carboxylic acids and others to the fermentation broth of S. avermitilis causes the microbes to accept these acids as substitutes and to make small amounts of avermectins containing these acids in form of new C-25 substituents. Examples of such new avermectin derivatives are:
Still additional avermectin derivatives are produced through artifical modification of the fermentation of Streptomyces avermitilis either by addition of metabolic inhibitors such as sinefungin (as described by Schulman et al., J. Antibiot. 1985 38, 1494-1498) or by mutation of the parent strain (as described by Schulman et al., Antimicrobial Agents and Chemotherapy, 1987, 31, 744-747, and by EP-276-131-A to Pfizer INC.). Some of these avermectin derivatives are still further modified and are missing one or two of the 3'- and 3"-O-methyl groups (Schulman et al., J. Antibiot. 1985, 38, 1494-1498). Examples for such derivatives are:
The fermentation products have been chemically modified in order to obtain further antiparasitic and insecticidal analogs with improved properties. Publications of such procedures in the scientific and patent literature have been reviewed by Fisher, M. H.; Mrozik, H. In Macrolide Antibiotics; Omura, S., Ed.; Academic: New York, 1984; pp 553-606, and by Davies, H. G.; Green, R. H. Nat. Prod. Rep., 1986, 3, 87-121.
For example, a group of semisynthetic avermectin derivatives were obtained by hydrogenating specifically the 22,23-double bond of avermectin B1 giving 22,23-dihydroavermectin B1 derivatives which have very potent anthelmintic and antiparasitic properties. Other examples of semisynthetic avermectin derivatives contain a 8,9-oxide group, a 4a-hydroxy or acyloxy group, a 23-keto group, which all are potent antiparasitic and insecticidal compounds.
These compounds may be used as starting materials for the compounds of the instant invention without further modification, or when containing additional reactive groups, which are not to be modified under the reaction conditions applied, only after protection of such with a suitable protecting group.